EP1476131A2 - Compositions and methods for delivery of skin cosmeceuticals - Google Patents
Compositions and methods for delivery of skin cosmeceuticalsInfo
- Publication number
- EP1476131A2 EP1476131A2 EP03711081A EP03711081A EP1476131A2 EP 1476131 A2 EP1476131 A2 EP 1476131A2 EP 03711081 A EP03711081 A EP 03711081A EP 03711081 A EP03711081 A EP 03711081A EP 1476131 A2 EP1476131 A2 EP 1476131A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- skin
- acid
- composition
- ammonium
- polymer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 49
- 238000000034 method Methods 0.000 title claims description 21
- 238000009472 formulation Methods 0.000 claims abstract description 18
- 150000007524 organic acids Chemical class 0.000 claims abstract description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 27
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 22
- 230000007423 decrease Effects 0.000 claims description 17
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 239000003995 emulsifying agent Substances 0.000 claims description 16
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- 150000003863 ammonium salts Chemical class 0.000 claims description 14
- 229920000642 polymer Polymers 0.000 claims description 14
- 229910021529 ammonia Inorganic materials 0.000 claims description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 13
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 12
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 11
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- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 3
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
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- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 3
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- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 description 4
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- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 3
- ICIDSZQHPUZUHC-UHFFFAOYSA-N 2-octadecoxyethanol Chemical compound CCCCCCCCCCCCCCCCCCOCCO ICIDSZQHPUZUHC-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
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- ZPWFUIUNWDIYCJ-UHFFFAOYSA-N propan-2-yl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC(C)C ZPWFUIUNWDIYCJ-UHFFFAOYSA-N 0.000 description 1
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- 229910001927 ruthenium tetroxide Inorganic materials 0.000 description 1
- 229940094944 saccharide isomerate Drugs 0.000 description 1
- 150000003870 salicylic acids Chemical class 0.000 description 1
- 230000008491 skin homeostasis Effects 0.000 description 1
- 230000008417 skin turnover Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- CRPCXAMJWCDHFM-UHFFFAOYSA-M sodium;5-oxopyrrolidine-2-carboxylate Chemical compound [Na+].[O-]C(=O)C1CCC(=O)N1 CRPCXAMJWCDHFM-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000002344 surface layer Substances 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 229960003500 triclosan Drugs 0.000 description 1
- GVPDNFYOFKBFEN-UHFFFAOYSA-N trimethyl(octadecoxy)silane Chemical compound CCCCCCCCCCCCCCCCCCO[Si](C)(C)C GVPDNFYOFKBFEN-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000005282 vitamin D3 Nutrition 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940021056 vitamin d3 Drugs 0.000 description 1
- 229940118846 witch hazel Drugs 0.000 description 1
- 238000007805 zymography Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/36—Carboxylic acids; Salts or anhydrides thereof
- A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/36—Carboxylic acids; Salts or anhydrides thereof
- A61K8/368—Carboxylic acids; Salts or anhydrides thereof with carboxyl groups directly bound to carbon atoms of aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/731—Cellulose; Quaternized cellulose derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/733—Alginic acid; Salts thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
- A61K8/8141—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
- A61K8/8147—Homopolymers or copolymers of acids; Metal or ammonium salts thereof, e.g. crotonic acid, (meth)acrylic acid; Compositions of derivatives of such polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
- A61K8/8141—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
- A61K8/8152—Homopolymers or copolymers of esters, e.g. (meth)acrylic acid esters; Compositions of derivatives of such polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/20—Chemical, physico-chemical or functional or structural properties of the composition as a whole
- A61K2800/28—Rubbing or scrubbing compositions; Peeling or abrasive compositions; Containing exfoliants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
Definitions
- the epidermal surface is acidic and has been the subject of studies on epidermal permeability and formation.
- the chemistry and function of dry skin, and moisturizers has been extensively reviewed (Loden and Howard, eds, 2000) in the context of understanding the factors involved in developing skin moisturizers and protective formulations.
- Skin homeostasis normally is maintained at about pH 5 allowing lipid barrier repairs. At more neutral or alkaline pH, skin repair is inhibited (Mauro, 1998). Studies have shown that there are racial differences in the stratum corneum pH gradient at least with respect to the surface layers. Significant differences between Caucasian and black African-American skin was reported by Berasdesca, et al. (1998), although no differences were found in the deeper stratum corneum layers.
- Mauro et al. states that the skin's lipid barrier is impeded at neutral pH, independent of ionic effects.
- Epidermal permeability barrier homeostasis requires the post-secretory processing of polar lipid precursors into nonpolar lipid products within the stratum corneum (SC) interstices by a family of lipid hydrolase enzymes.
- SC stratum corneum
- beta-glucocerebrosidase beta-glucocerebrosidase
- permeability barrier recovery by assessing changes in transepidermal water loss (TEWL), SC membrane ultrastructure utilizing ruthenium tetroxide (Ru0 ) postfixation, and beta-GlcCer'ase activity by in situ zymography at an acidic vs. neutral pH.
- Barrier recovery proceeded normally when acetone-treated skin was exposed to solutions buffered to an acidic pH.
- the initiation of barrier recovery was slowed when treated skin was exposed to neutral or alkaline pH, regardless of buffer composition.
- enhancement of the alkaline buffer-induced delay in barrier recovery occurred with Ca 2+ and K + inclusion in the buffer.
- an acidic skin care agent is desirable for the reasons given above, but many acidic agents that have been used in skin products have a pH low enough to cause irritation or slight burning. The irritation and burning can be cumulative over repeated application.
- the acids are effective at low pH, however, they are not available in formulations for periods of time of at least several hours at optimal effective pHs.
- a stable shelf-life is necessary for skin care formulations, which generally requires a pH of no lower than 6.0.
- a pH of 6.0 or more insures that the product is stable, but is too high to promote effective rebuilding of the skin's protective barrier.
- the invention recognizes the need to provide an environment of below pH 5.5, and preferably between about pH 4.5 and 5.0 to promote activity of the skin enzymes involved in repairing a damaged lipid skin barrier.
- the invention addresses the problem of providing an ideal pH for cosmeceuticals and skin treatments. This is accomplished by providing an ammonium salt of a selected weak organic acid to the skin in a formulation that allows slow evaporation after skin contact, resulting in release of ammonia and a gradual decrease in pH at or below 5.5 The decrease in pH may take place over several hours. Active ingredient delivery of pharmaceutical ingredients and/or skin sloughing is enhanced as the pH becomes more acidic, but there is no irritation because the decrease in pH is gradual. At some point the pH of the parent acid is reached, adding a measure of control over the final pH.
- Selected acids are formulated into vehicles in the form of solutions, lotions, and/or creams that are well recognized for use in the preparation of skin products.
- the final products are adjusted to a pH value of 6.5-6.9 with an aqueous ammonia solution. This results in the formation of the ammonium salt(s) so neutralized.
- certain salts of alpha hydroxy acids such as the sodium, potassium, ammonium, diethanolamine, triethanolamine etc. salts are humectants and when applied to the skin they are safe and non- irritating and are powerful skin moisturizers; but because the pH is at neutrality, these salts remain active only as humectants and will not enhance skin sloughing of scaly dry skin or enhance skin turnover.
- the salts applied are the ammonium salts
- the ammonia gradually evaporates from the product, the pH drops and the moisturizer turns into an active acid for enhancing skin sloughing and turnover and in the case of salicylic acid becomes an active agent for the treatment of acne.
- the advantage of this system is that the pH drop occurs over time, typically three to four hours and so the product is never irritating to the skin and the activity increases with time.
- a self-adjusting emulsifier may be employed. As the emulsifier in the formulation evaporates, the composition self-adjusts to a lower pH which will typically be in the range of 3.5-5.5 matching the stratum corneum pH required for haling and enzyme production to repair the lipid barrier.
- Delivery may be formulated in liposomes, ceramide III, triclosan, avobenzone, oxybenzone or in other numerous ways accepted in the art for formulating cosmeceuticals. 3.0 BRIEF DESCRIPTION OF THE DRAWINGS
- FIG. 1 shows the natural pH repair zone for skin.
- FIG. 2 schematically illustrates the moisture uptake by a polymer layer at the skin surface and concomitant release of active ingredients.
- moisturizers are formulated and packaged for long shelf life. Initially the pH is adjusted to about 6.0-7.5 to provide the stability required. This is accomplished by providing an ammonium salt of a selected weak organic acid to the skin in a formulation that allows slow evaporation after skin contact, resulting in release of ammonia and a gradual decrease in pH at or below 5.5 The decrease in pH may take place over several hours. Active ingredient delivery of pharmaceutical ingredients and/or skin sloughing is enhanced as the pH becomes more acidic, but there is no irritation because the decrease in pH is gradual. At some point the pH of the parent acid is reached, adding a measure of control over the final pH.
- Example 1 Skin moisturizing and sloughing preparation
- Ammonium stearate was used as the emulsifying agent. Glycolic acid was neutralized with ammonia to form the ammonium salt. The salt was then formulated into a pharmaceutically acceptable cream selected for non- irritation to the skin and typically used in preparing cosmetic formulations.
- An all over moisturizer was prepared(Example 1), with similar preparations prepared for the face (Example 2), as an acne treatment cream (Example 3), for the fragile eye area (Example 4) and as a night cream (Example 5).
- the composition of Examples 1-3 is given above. For Examples 4 and 5, the different preparations used different concentrations of inactive ingredients that are well known in the art for producing moisturizing creams.
- the ammonia gradually evaporated to form glycolic acid. The acid began sloughing of dead cells with greater activity over a period of 3-4 hours as the pH of the composition gradually decreased over this period to about 4.5.
- Table 1 illustrates the change in pH over time of several cosmetic products by comparison to the disclosed product. It can be seen that the pH of Examples 1-4 decreases to 4.5 and remains at that level for several hours in contrast with comparable products whose pH shows little change from neutral. TABLE 1 pH*
Abstract
New cosmetic compositions are disclosed that are effective both as moisturizers and skin sloughing agents. The compositions contain neutralized weak organic acids that when applied over time to the skin in appropriate formulations will gradually increase in acidity to pH 5.5 or less, for example about pH 4.5, without causing skin irritation while exhibiting increasing activity in skin renewal effects.
Description
COMPOSITIONS AND METHODS FOR DELIVERY OF SKIN
COSMECEUTICALS
1.0 BACKGROUND ART
1.1 FIELD OF THE INVENTION
The invention concerns compositions and methods for formulating and delivering cosmeceutical skin preparations. The disclosed compositions are particularly adapted for delivery of acidic agents for skin renewal and treatment agents.
1.2 DESCRIPTION OF RELATED ART
Human skin acts as a protective barrier to both physical and chemical insults. The properties of the cutaneous layer are important to the cosmetic industry in developing effective and safe skin preparations in addition to medical concerns in treating damage to. the skin surface in conditions such as acne.
The epidermal surface is acidic and has been the subject of studies on epidermal permeability and formation. The chemistry and function of dry skin, and moisturizers has been extensively reviewed (Loden and Howard, eds, 2000) in the context of understanding the factors involved in developing skin moisturizers and protective formulations.
Skin homeostasis normally is maintained at about pH 5 allowing lipid barrier repairs. At more neutral or alkaline pH, skin repair is inhibited (Mauro, 1998). Studies have shown that there are racial differences in the stratum corneum pH gradient at least with respect to the surface layers. Significant differences between Caucasian and black African-American skin was reported by
Berasdesca, et al. (1998), although no differences were found in the deeper stratum corneum layers.
Mauro et al. states that the skin's lipid barrier is impeded at neutral pH, independent of ionic effects. Epidermal permeability barrier homeostasis requires the post-secretory processing of polar lipid precursors into nonpolar lipid products within the stratum corneum (SC) interstices by a family of lipid hydrolase enzymes. A specific requirement for beta-glucocerebrosidase (beta-GlcCer'ase), which exhibits a distinct optimum acidic pH, is particularly well documented. The investigators sought to determine whether the recovery of the barrier after acute insults requires acidification of the SC. They examined permeability barrier recovery by assessing changes in transepidermal water loss (TEWL), SC membrane ultrastructure utilizing ruthenium tetroxide (Ru0 ) postfixation, and beta-GlcCer'ase activity by in situ zymography at an acidic vs. neutral pH. Barrier recovery proceeded normally when acetone-treated skin was exposed to solutions buffered to an acidic pH. In contrast, the initiation of barrier recovery was slowed when treated skin was exposed to neutral or alkaline pH, regardless of buffer composition. In addition, enhancement of the alkaline buffer-induced delay in barrier recovery occurred with Ca2+ and K+ inclusion in the buffer. Moreover, the pH- dependent alteration in barrier recovery appeared to occur through a mechanism that was independent of Ca2+ or K+ controlled lamellar body secretion, since both the formation and secretion of lamellar bodies proceeded comparably at pH 5.5 and pH 7.4. Exposure to pH 7.4 (but not pH 5.5) resulted in both the persistence of immature, extracellular lamellar membrane structures, and a marked decrease in the in situ activity of beta- GlcCer'ase. These results suggest first that an acidic extracellular pH is necessary for the initiation of barrier recovery, and second that the delay in barrier recovery is a consequence of inhibition of post-secretory lipid processing.
Kligman (2000) states "...our concept of humectants (as moisturizers) falls short of explaining how they work. It is worth repeating that used alone they are not much good. It is only when they are properly formulated with other ingredients that their potential benefits are realized. Other factors such as pH also have to be taken into account, because proteases which lead to orderly desquamation of horny cells within the stratum corneum are activated only at acid pHs of 4 to 5. Also the various hydrolytic enzymes, which are found in the stratum corneum and which are essential to the formation of the intercomeocyte lipids that establish the impermeability of the barrier, are activated only at acid pHs" (Kligman, 2000).
Feingold and Elias (2000) state that the epidermal surface has been known for many years to be acidic, but the role of this acidic pH of the stratum corneum in barrier homeostasis was unknown. It is well recognized that β- glucocerebrosidase is most active at pH 5.5. Recently, we have examined barrier recovery of an acidic vs. neutral pH. Barrier recovery proceeded normally when acetone treated skin was exposed to solutions buffered to an acidic pH. In contrast, barrier recovery was delayed when treated skin was exposed to neutral or alkaline pH regardless of buffer composition" (in Dermatology, eds. Loden and Maibach, 2000). These results indicate that an acidic extracellular pH in the SC is required for normal extracellular lipid processing and normal barrier homeostasis.
The majority of marketed skin treatment preparations use emulsifying agents that are non-volatile and accordingly remain on the skin until removed by cleansing. Most facial care cosmetics are formulated with about 5-7% emulsifying agents, at a pH of 6.5-8.0 to insure product stability, and contain on average about 75% water. After application to the skin the water used in the formulation evaporates off the skin quickly, leaving up to approximately a 20% concentration of emulsifying agents on the skin. This high level of emulsifying agent is capable of emulsifying the natural lipids in the skin which can be removed on cleansing the skin. The net result is detrimental to the
skin for two reasons: the residual pH of 6.5 to 8.0 is not favorable for the repair of the skin's lipid barrier layer and the residual high level of emulsifying agents is conducive to removal of the natural lipids in the skin leading to an even drier skin condition. The stress of the emulsifying agent residue causes overstimulation of the skin, increased oil production, irritation and blemishes. Stronger emulsions are difficult to neutralize for older skin and sensitive skin. Harsh emulsifiers may actually damage skin by dissolving the skin's protective lipid barrier, which is essential to healthy looking skin. Additionally, perspiration may remove the active ingredients deposited on the skin.
1.3 DEFICIENCIES IN THE PRIOR ART
The inventors have observed that an acidic skin care agent is desirable for the reasons given above, but many acidic agents that have been used in skin products have a pH low enough to cause irritation or slight burning. The irritation and burning can be cumulative over repeated application. The acids are effective at low pH, however, they are not available in formulations for periods of time of at least several hours at optimal effective pHs. A stable shelf-life is necessary for skin care formulations, which generally requires a pH of no lower than 6.0. A pH of 6.0 or more insures that the product is stable, but is too high to promote effective rebuilding of the skin's protective barrier.
2.0 SUMMARY OF THE INVENTION
The invention recognizes the need to provide an environment of below pH 5.5, and preferably between about pH 4.5 and 5.0 to promote activity of the skin enzymes involved in repairing a damaged lipid skin barrier.
The invention addresses the problem of providing an ideal pH for cosmeceuticals and skin treatments. This is accomplished by providing an
ammonium salt of a selected weak organic acid to the skin in a formulation that allows slow evaporation after skin contact, resulting in release of ammonia and a gradual decrease in pH at or below 5.5 The decrease in pH may take place over several hours. Active ingredient delivery of pharmaceutical ingredients and/or skin sloughing is enhanced as the pH becomes more acidic, but there is no irritation because the decrease in pH is gradual. At some point the pH of the parent acid is reached, adding a measure of control over the final pH.
As used herein, the disclosed preparations and formulations are termed cosmeceuticals, a hybrid term incorporating the concept of improving skin appearance by application of active ingredients that often serve a therapeutic role. Certain of the particular formulations disclosed have application in treatment of skin conditions with over the counter (OTC) drugs, such as the use of salicylic acid for acne treatment. The disclosed formulations provide, among other benefits, a method of controlling pH of salicylic acid on the skin to avoid irritation and burning and by causing a gradual lowering of pH from the neutral value at the initial application.
The disclosed novel product delivery system has many advantages over conventional products in regard to safety, efficacy and longevity of action.
There are many weak organic acids that are beneficial to the skin, such as salicylic acid, glycolic acid, lactic acid, malic acid, citric acid, tartaric acid and the like but which have a very low pH and can be irritating. Salicylic acid is a beta hydroxy acid and is an approved drug at 2% for the treatment of acne. Other acids include alpha and mixed alpha and beta-hydroxy acids that are used to slough off the top dead layers of the skin to improve skin appearance.
Selected acids are formulated into vehicles in the form of solutions, lotions, and/or creams that are well recognized for use in the preparation of skin products. The final products are adjusted to a pH value of 6.5-6.9 with an
aqueous ammonia solution. This results in the formation of the ammonium salt(s) so neutralized. It is well known that certain salts of alpha hydroxy acids such as the sodium, potassium, ammonium, diethanolamine, triethanolamine etc. salts are humectants and when applied to the skin they are safe and non- irritating and are powerful skin moisturizers; but because the pH is at neutrality, these salts remain active only as humectants and will not enhance skin sloughing of scaly dry skin or enhance skin turnover. However, when the salts applied are the ammonium salts, as in the present invention, after application to the skin the ammonia gradually evaporates from the product, the pH drops and the moisturizer turns into an active acid for enhancing skin sloughing and turnover and in the case of salicylic acid becomes an active agent for the treatment of acne. The advantage of this system is that the pH drop occurs over time, typically three to four hours and so the product is never irritating to the skin and the activity increases with time.
It is also possible to build into these systems salts of skin protective polymers that are water soluble at pH 6 to pH 7 but which become insoluble at pH values below pH 5. Thus ammonium carboxymethyl cellulose, ammonium alginate, ammonium carragheenate, ammonium polyacrylate, ammonium VA Acrylate and the like are water soluble but after application to the skin the ammonia evaporates and a thin layer of water insoluble polymer is left on the skin which acts as a barrier to protect the skin, enhances skin moisturization and, because it is water insoluble, holds other important ingredients in contact with the skin.
There is one further major advantage that accrues in using the ammoniated system. It has been shown that the skin enzymes involved in repairing a damaged lipid skin barrier are only active at a pH of below 5.5. Almost every skin care preparation on the market today is at a pH of 6.5-7.5 and remains at this pH for as long as it remains on the skin thus interfering with the enzymes required for rebuilding the protective lipid barrier. In the disclosed
compositions, the ammonia evaporates and the pH reaches the optimum level for enzymatic activity and skin barrier repair.
In certain embodiments, a self-adjusting emulsifier may be employed. As the emulsifier in the formulation evaporates, the composition self-adjusts to a lower pH which will typically be in the range of 3.5-5.5 matching the stratum corneum pH required for haling and enzyme production to repair the lipid barrier.
There are two types of emulsions: oil in water and water in oil. Formulations can be created to deliver 100% of the therapeutic ingredients on application to the skin and hold the ingredients when a polymer complex is used. Polymer based moisturizers create a protective barrier on the skin that captures moisture normally lost by the skin but at the same time allow the skin to readily exchange oxygen and carbon dioxide, unlike oil based moisturizers. The moisture cushion allows water to soften the skin.
The basic compositions may include numerous other ingredients, depending on the requirements of a particular skin type. Vitamins such as vitamin A palmitate, pro-vitamin B-5, vitamin E, vitamin D3 and vitamin C are illustrative of beneficial vitamins that may be added. Herbal and botanicals may also be included with the ammonium salts, including green tea, aloe vera, ivy extract chamomile, watercress, silk, sea kelp, meadowsweet, ginkgo biloba, spirulina maxima, passion flower, witch hazel, pea extract, algae extract, apple, sugar cane, avocado oil, jojoba oil and evening primrose oil.
Delivery may be formulated in liposomes, ceramide III, triclosan, avobenzone, oxybenzone or in other numerous ways accepted in the art for formulating cosmeceuticals.
3.0 BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the natural pH repair zone for skin.
FIG. 2 schematically illustrates the moisture uptake by a polymer layer at the skin surface and concomitant release of active ingredients.
4.0 DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
The present invention relates to cosmetic moisturizing preparations that adjust from higher to lower pH after application. These formulations typically provide a pH level of about 4.5 by incorporating a fatty acid salt as a major ingredient. The salt is converted at least in part to a fatty acid which lowers the pH at the skin surface. This is illustrated in Table 1 where pH changes for selected moisturizing creams from different brands are compared.
Most moisturizers are formulated and packaged for long shelf life. Initially the pH is adjusted to about 6.0-7.5 to provide the stability required. This is accomplished by providing an ammonium salt of a selected weak organic acid to the skin in a formulation that allows slow evaporation after skin contact, resulting in release of ammonia and a gradual decrease in pH at or below 5.5 The decrease in pH may take place over several hours. Active ingredient delivery of pharmaceutical ingredients and/or skin sloughing is enhanced as the pH becomes more acidic, but there is no irritation because the decrease in pH is gradual. At some point the pH of the parent acid is reached, adding a measure of control over the final pH.
5.0 EXAMPLES
Example 1 — Skin moisturizing and sloughing preparation
Part i Percent (w/w)
Stearic Acid 2.55
Cetyl Alcohol 1.70
Glyceryl Stearate 1.25
Isopropyl Stearate 0.42 Caprylic/Capric Triglyceride 0.25
Lanolin 0.42
Part 2
Deionized Water qs 100.00
Glycolic Acid (70%)* 7.00 Ammonium Hydroxide (28%) qs to pH 6.7
Part 3
Propylene Glycol 7.50
SD Alcohol 40-2 5.00
Polyhydroxyethylmethacrylate 0.50 Steareth-20 0.02
Part 4
Germaben II (ISP) 1.00
Part 5
Fragrance 0.10
Example 2 — Skin Facial Moisturizing and Sloughing Preparation
Part i Percent (w/w)
Octyl Methoxy Cinnamate 7.00 Benzophenone-3 3.00
Avobenzone 2.00
Stearic Acid 2.30
Cetyl Alcohol 1.50
Glyceryl Stearate 1.50 Dimethicone 1.00
Tocopheryl Acetate Cosmetic Grade 0.50
C12-15 Alkyl Benzoate 0.35
Stearoxytrimethylsilane 0.25 Part 2 Vitamin A Palmitate 0.10
Tetrahexadecyl Ascorbate 0.10
Part 3
Deionized Water qs 100.00
Lactic Acid (88%)* 5.00
Disodium Edetate 0.20
Part 4
Deionized Water 9.80
Propylene Glycol 7.50
SD Alcohol 40-2 5.00
Polyhydroxyethylmethacrylate 0.50
Aloe Vera Gel (200X) 0.10
Steareth-20 0.02
Part 5
Ammonia Solution Strong (27%) (26° Baume) qs to pH 6.7-6.9
Example 3 — Acne Moisturizinq and Treatment Cream
Caprylic/Capric Triglyceride 5.00
Glyceryl Stearate 3.00
Salicylic Acid* 2.00
Cetyl Alcohol 1.50
Stearic Acid 1.30
Beeswax 1.00
Cholesterol 0.25
BHT 0.05
Part 2
Deionized Water 47.17
Propylene Glycol 5.00
Sodium Hyaluronate 3.00
Sodium PCA 2.00
Saccharide Isomerate 1.00
Disodium Edetate 0.20
Part 3
Deionized Water 9.80
Propylene Glycol 7.50
SD Alcohol 40-2 5.00
Polyhydroxyethylmethacrylate 0.50
Aloe Vera Gel (200X) 0.10
Steareth-20 0.02
Part 4
Ammonia Solution Strong (27%) (26° Baume) qs to pH 6.7-6.9
* While the examples shown above utilize glycolic, lactic and salicylic acids, this does not preclude the use of other hydroxy or non-hydroxy acids having a moisturizing, skin sloughing or skin treatment effect.
Ammonium stearate was used as the emulsifying agent. Glycolic acid was neutralized with ammonia to form the ammonium salt. The salt was then formulated into a pharmaceutically acceptable cream selected for non- irritation to the skin and typically used in preparing cosmetic formulations. An all over moisturizer was prepared(Example 1), with similar preparations prepared for the face (Example 2), as an acne treatment cream (Example 3), for the fragile eye area (Example 4) and as a night cream (Example 5). The composition of Examples 1-3 is given above. For Examples 4 and 5, the different preparations used different concentrations of inactive ingredients that are well known in the art for producing moisturizing creams. Upon application to the skin, the ammonia gradually evaporated to form glycolic acid. The acid began sloughing of dead cells with greater activity over a period of 3-4 hours as the pH of the composition gradually decreased over this period to about 4.5.
Table 1 illustrates the change in pH over time of several cosmetic products by comparison to the disclosed product. It can be seen that the pH of Examples 1-4 decreases to 4.5 and remains at that level for several hours in contrast with comparable products whose pH shows little change from neutral.
TABLE 1 pH*
*ColorpHast pH 0-14 pH paper, EM Science, Gibbstown, NJ 08027 was used for this test
** Registered Trademarks
The examples of the present invention were tested in 8 and 12 hour clinical studies, which proved extended performance as well as a reduction in pH. After 8 hours in a sweat booth, only 4% of the moisturizer had been removed from the skin. In addition, immersion testing proved outstanding results. At the end of the day, positive moisturization was felt, whereas most formulas fail in a few hours. The example products did not need to be altered for oily, normal, or dry skin, as the controlled release of the acids were found to balance and normalize all skin types, even the most sensitive skin.
REFERENCES
Berardesca, E., Pirot, F. Singh, M. and Maibach, H. "Differences in stratum corneum pH gradient when comparing white Caucasian and black African-American skin" Brit. J. Dermatology, 139, 855-857 (1998).
Feingold, K.R. and Elias, P.M. in Dermatology: Clinical & Basic Science Series, eds. Marie Loden and Howard I. Maibach, CRC Press, 45-58, 2000
Kligman, A. in Dry skin and Moisturizers, Ed. Loden and Maibach, CRC Press, Boca Raton, 2000, p. 8
Maura, T. Arch Dermatol. Res 290(4): 215-222, 1998
Claims
1. A composition comprising an ammonium salt of a weak organic acid combined with a time release polymer base formulation wherein the composition releases ammonia when in skin contact to provide a gradual decrease in pH to 5.5 or less.
2. The composition of claim 1 , wherein the pH of the composition gradually decreases to between 2.0 and 5.0 when in skin contact.
3. The composition of claim 2, wherein the pH of the composition gradually decreases to between 4.0 and 4.5 when in skin contact.
4. The composition of claim 1 , wherein the weak organic acid is selected from salicylic acid, glycolic acid, lactic acid, malic acid, citric acid, and tartaric acid.
5. The composition of claim 1 , wherein the weak organic is an alpha or beta hydroxy acid.
6. The composition of claim 5, wherein the beta hydroxy acid is salicylic acid.
7. The composition of claim 1 , wherein the time release polymer base formulation is pharmaceutically acceptable.
8. The composition of claim 1 , wherein said formulation is a solution, lotion or cream.
9. A method of enhancing skin sloughing, comprising formulating a selected organic weak acid with a pharmaceutically acceptable emulsifying agent, neutralizing the acid with ammonia to a pH of 6.5-
6.9 to form a dispersed ammonium salt, applying said ammonium salt to skin wherein the pH gradually lowers to 5.5 or less as ammonia evaporates causing a gradual enhancement of skin sloughing.
10. The method of claim 9, wherein the pH of the composition gradually decreases to between 2.0 and 5.0 when in skin contact.
11. The method of claim 10, wherein the pH of the composition gradually decreases to between 4.0 and 4.5 when in skin contact.
12. The method of claim 9, wherein the emulsifying agent is a volatile emulsifying polymer that evaporates over a period of time to leave a water insoluble polymer on skin surface.
13. The method of claim 9, wherein the weak organic acid is selected from the group consisting of salicylic acid, glycolic acid, lactic acid, malic acid, citric acid and tartaric acid.
14. The method of claim 9, wherein the pH is lowered over a period of 3-4 hours.
15. The method of claim 9, wherein the weak organic acid is an alpha or beta hydroxy acid.
16. The method of claim 15, wherein the beta hydroxy acid is salicylic acid.
17. The method of claim 9, further comprising a polymer that is water soluble at or near neutral pH, wherein the polymer becomes insoluble at a pH near or below pH 5.
18. The method of claim 17, wherein the water soluble polymer is ammonium carboxymethyl cellulose, ammonium alginate, ammonium carragheenate, ammonium polyacrylate, or ammonium VA/Acrylate.
19. A kit comprising the composition of claim 1 , in suitable container form and directions for applying said composition for skin moisturization and sloughing.
20. The kit of claim 19, wherein the composition is ammonium salicylate in a skin protective polymer.
21. The kit of claim 20, wherein the skin protective polymer is water soluble at neutral pH and insoluble at pH near or below pH 5.
22. The kit of claim 20, wherein the skin protective polymer is ammonium carboxymethyl cellulose, ammonium alginate, ammonium carragheenate, ammonium polyacrylate, or ammonium VA/Acrylate .
23. A method for treating acne, comprising applying an ammonium salt of salicylic acid dispersed in a formulation with an emulsifying agent and a lipid with sufficient water to allow gradual release of ammonia when in skin contact wherein the pH of the skin surface gradually lowers to a pH of 5.5 or less.
24. The method of claim 23, wherein the skin surface pH gradually decreases to between 2.0 and 5.0 when the composition is in skin contact.
25. The method of claim 24, wherein the skin surface pH gradually decreases to between 4.0 and 4.5 when the composition is in skin contact.
26. The method of claim 23, wherein the emulsifying agent is combined with a polymer and wherein the emulsifying agent evaporates over a period of time to leave a water insoluble emollient and/or polymer on the skin surface.
27. A method of enhancing skin sloughing, comprising formulating a selected organic weak acid with a pharmaceutically acceptable emulsifying agent, neutralizing the acid with ammonia to a pH of 6.5- 6.9 to form a dispersed ammonium salt, applying said ammonium salt to skin wherein the pH gradually lowers to 5.5 or less as ammonia evaporates causing a gradual enhancement of skin sloughing.
28. The method of claim 27, wherein the pH gradually decreases to between 2.0 and 5.0 when the ammonium salt is in skin contact.
29. The method of claim 28, wherein the pH gradually decreases to between 4.0 and 4.5 when the ammonium salt is in skin contact.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US35746602P | 2002-02-15 | 2002-02-15 | |
US357466P | 2002-02-15 | ||
PCT/US2003/004718 WO2003070180A2 (en) | 2002-02-15 | 2003-02-14 | Compositions and methods for delivery of skin cosmeceuticals |
Publications (2)
Publication Number | Publication Date |
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EP1476131A2 true EP1476131A2 (en) | 2004-11-17 |
EP1476131A4 EP1476131A4 (en) | 2007-03-07 |
Family
ID=27757624
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP03711081A Withdrawn EP1476131A4 (en) | 2002-02-15 | 2003-02-14 | Compositions and methods for delivery of skin cosmeceuticals |
Country Status (6)
Country | Link |
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US (1) | US6984391B2 (en) |
EP (1) | EP1476131A4 (en) |
JP (1) | JP2005519935A (en) |
AU (1) | AU2003215264A1 (en) |
CA (1) | CA2512020A1 (en) |
WO (1) | WO2003070180A2 (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050281853A1 (en) * | 2002-02-15 | 2005-12-22 | Fox Charles A | Skin compatible cosmetic compositions and delivery methods therefor |
US8114386B2 (en) * | 2006-05-12 | 2012-02-14 | 3M Innovative Properties Company | Topical insect repellent composition and method of application |
WO2009051486A1 (en) * | 2007-10-18 | 2009-04-23 | Sara Lee/De N.V. | Shaving composition with skincare properties |
CN110785161B (en) | 2017-06-23 | 2023-06-20 | 宝洁公司 | Compositions and methods for improving the appearance of skin |
WO2020010036A1 (en) | 2018-07-03 | 2020-01-09 | The Procter & Gamble Company | Method of treating a skin condition |
US10959933B1 (en) | 2020-06-01 | 2021-03-30 | The Procter & Gamble Company | Low pH skin care composition and methods of using the same |
WO2021247496A1 (en) | 2020-06-01 | 2021-12-09 | The Procter & Gamble Company | Method of improving penetration of a vitamin b3 compound into skin |
CN114081848A (en) * | 2021-11-19 | 2022-02-25 | 上海琪维生物科技有限公司 | Composition for skin care and application thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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US4197316A (en) * | 1975-07-23 | 1980-04-08 | Scott Eugene J Van | Treatment of dry skin |
US4285973A (en) * | 1979-07-20 | 1981-08-25 | Alberto-Culver Company | Liquid composition for application to the skin |
FR2604625A1 (en) * | 1986-10-02 | 1988-04-08 | Jouvance Labo Cosmetologie Bio | Process for the manufacture of cosmetic compositions based on alginic acid and cosmetic compositions obtained |
FR2773074A1 (en) * | 1997-12-30 | 1999-07-02 | Led Evolution Dermatolog | Composition containing an alpha-hydroxy acid and a ceramide or ceramide precursor for topical treatment of dermatological disorders |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5920217A (en) * | 1982-07-27 | 1984-02-01 | Kawaken Fine Chem Co Ltd | Aqueous jellylike composition stably containing urea |
JPS61152612A (en) * | 1984-12-26 | 1986-07-11 | Daicel Chem Ind Ltd | Oily cosmetic |
FR2607498B1 (en) * | 1986-12-01 | 1991-04-05 | Oreal | NOVEL LIPOPHILIC SALICYLATES OF QUATERNARY AMMONIUMS, THEIR USE IN COSMETICS AND DERMOPHARMACY |
US5073372A (en) * | 1990-11-30 | 1991-12-17 | Richardson-Vicks, Inc. | Leave-on facial emulsion compositions |
US5997887A (en) * | 1997-11-10 | 1999-12-07 | The Procter & Gamble Company | Skin care compositions and method of improving skin appearance |
-
2003
- 2003-02-14 WO PCT/US2003/004718 patent/WO2003070180A2/en active Application Filing
- 2003-02-14 EP EP03711081A patent/EP1476131A4/en not_active Withdrawn
- 2003-02-14 AU AU2003215264A patent/AU2003215264A1/en not_active Abandoned
- 2003-02-14 US US10/366,845 patent/US6984391B2/en not_active Expired - Fee Related
- 2003-02-14 JP JP2003569140A patent/JP2005519935A/en active Pending
- 2003-02-14 CA CA002512020A patent/CA2512020A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4197316A (en) * | 1975-07-23 | 1980-04-08 | Scott Eugene J Van | Treatment of dry skin |
US4285973A (en) * | 1979-07-20 | 1981-08-25 | Alberto-Culver Company | Liquid composition for application to the skin |
FR2604625A1 (en) * | 1986-10-02 | 1988-04-08 | Jouvance Labo Cosmetologie Bio | Process for the manufacture of cosmetic compositions based on alginic acid and cosmetic compositions obtained |
FR2773074A1 (en) * | 1997-12-30 | 1999-07-02 | Led Evolution Dermatolog | Composition containing an alpha-hydroxy acid and a ceramide or ceramide precursor for topical treatment of dermatological disorders |
Non-Patent Citations (3)
Title |
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DATABASE WPI Week 198411 Derwent Publications Ltd., London, GB; AN 1984-065031 XP002414955 & JP 59 020217 A (KAWAKEN FINE CHEM CO LTD) 1 February 1984 (1984-02-01) * |
DATABASE WPI Week 198634 Derwent Publications Ltd., London, GB; AN 1986-221930 XP002414956 & JP 61 152612 A (DAICEL CHEM IND LTD) 11 July 1986 (1986-07-11) * |
See also references of WO03070180A2 * |
Also Published As
Publication number | Publication date |
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EP1476131A4 (en) | 2007-03-07 |
CA2512020A1 (en) | 2003-08-28 |
WO2003070180A3 (en) | 2003-12-24 |
WO2003070180A2 (en) | 2003-08-28 |
JP2005519935A (en) | 2005-07-07 |
AU2003215264A1 (en) | 2003-09-09 |
AU2003215264A8 (en) | 2003-09-09 |
US20030165552A1 (en) | 2003-09-04 |
US6984391B2 (en) | 2006-01-10 |
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